The overall objectives of this research application is the development of new synthetic methodology involving a new process for creating asymmetric carbon centers. The long range goal of the research is the application of this chemistry to the synthesis of new and more selective antitumor agents and anticancer/antiviral agents. The specific aims of the application include the enantioselective synthesis of several members of the physostigmine alkaloid family including eseroline, physovenine, chimonanthine and hodgkinsine. This class of compounds contains numerous members with anticancer activity and some that are anticholinesterases and miotics. Using analogous synthetic methodology, more efficient routes to enantiomerically pure aflatoxins will be sought. These compounds are potent carcinogens, and pharmacological studies of these compounds provide a better understanding of carcinogenesis. Other specific aims include the preparation of simple analogs of sesquiterpene lactones of the germacranolide and cembranolide types. These molecules are directed towards new macrocyclic lactones with tumor inhibitory activity. A major new thrust of this application involves the synthesis of optically active precursors for C-nucleosides and N-nucleosides such as pyrazomycin and the polyoxins respectively. Pyrazomycin also has known anti-HVS activity. Our new synthetic methodology allows for a unique assemblage of chiral riboside and deoxyriboside systems. Additional target molecules in this work include small peptide immunostimulants such as Bestatin and Amastatin. Finally, work will continue on refinement and modifications of the epipodophyllotoxin derivatives VP-16 and VM-26 which are clinically used antitumor agents for lung carcinomas. New compounds are to be tested at Warner-Lambert/Parke Davis in Ann Arbor or the Michigan Cancer Center of the University of Michigan.